Asymmetric syntheses of potential anti-malarial drugs designed from Fieser's 2-hydroxy-3-(2-methyloctyl)naphthalene-1,4-dione

Article abstract of DOI:10.24820/ARK.5550190.P011.206

We describe asymmetric syntheses of the potential anti-malarial drugs (S)-2-(8-fluoro-2-methyloctyl)-3-hydroxynaphthalene-1,4-dione, (S)-2-hydroxy-3-(8-trifluoromethyl-2-methyloctyl)-3-hydroxynaphthalene-1,4-dione, and (S)-2-hydroxy-3-(2-methyloctyl)naphthalene-1,4-dione, which are patterned after Fieser's “10576,” known to be active against the mosquito borne parasite Plasmodium falciparum.

Full text of DOI:10.24820/ARK.5550190.P011.206

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Asymmetric syntheses of potential anti-malarial drugs designed from
Fieser's 2-hydroxy-3-(2-methyloctyl)naphthalene-1,4-dione
Louise M. Fisher, Eliana E. Kim, Nicolai V. Moskalev, and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Email: ggribble@dartmouth.edu
In celebration of the outstanding chemistry of Jan Bergman and for 50 years of his friendship
and in memory of Bernard L. Trumpower
Received mm-dd-yyyy
Accepted mm-dd-yyyy
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Abstract
We describe asymmetric syntheses of the potential anti-malarial drugs (S)-2-(8-fluoro-2-methyloctyl)-3-
hydroxynaphthalene-1,4-dione, (S)-2-hydroxy-3-(8-trifluoromethyl-2-methyloctyl)-3-hydroxynaphthalene-1,4-
dione, and (S)-2-hydroxy-3-(2-methyloctyl)naphthalene-1,4-dione, which are patterned after Fieser’s “10576,”
known to be active against the mosquito borne parasite Plasmodium falciparum.
Keywords: Atovaquone, anti-malarials, asymmetric synthesis, 2-hydroxynaphthalene-1,4-dione
DOI: https://doi.org/10.24820/ark.5550190.p011.206Page 1
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Introduction
Malaria, a disease transmitted by the mosquito borne parasite Plasmodium falciparum, is generally considered
to be the most serious infectious disease in the world. It has been estimated by some parasitologists that 50%
of the human beings ever born were killed by this parasite.1 It currently kills more than 400,000 people
annually, more than half of whom are children under the age of 5 in sub-Saharan Africa.2 Unfortunately, the
malaria parasite, through mutations has become resistant to known drugs, including atovaquone (1), a 2-
hydroxynaphthalene-1,4-dione (2-hydroxy-1,4-naphthoquinone), which is an active component in Proguanil, a
drug used to treat parasitic infections since the 1990s.3 Moreover, naphthoquinones, such as derivatives of
lawsone (2), lapachol (3), and -lapachone (4), and others, have been of great interest in recent years as
possible new agents to treat parasitic, fungal, and other infections, including malaria (Figure 1). 4-10
Figure 1. Structures of antimalarial naphthoquinones 1-4
In connection with our interest in developing novel anti-malarial drugs based on lapachones and related
2-hydroxynaphthalene-1,4-diones11-13 as inhibitors of the cytochrome bc1 complex,14 which is a respiratory
enzyme essential for the Plasmodium falciparum parasite, we prepared the atovaquone analogue (S)-2-
hydroxy-3-(2-methyloctyl)naphthalene-1,4-dione (“S-10576”) (5), which was first synthesized and screened in
1948 by Fieser in racemic form (“M-285”) and found to have curative action against malarial infections.15
Although 5 is more potent than atovaquone, it undergoes rapid metabolism in humans by bis-hydroxylation of
the two terminal alkyl groups to give a 2-methylheptyl carboxylic acid side chain.16 To preclude this oxidative
metabolism of 5, we synthesized the fluorinated analogues (S)-2-(8-fluoro-2-methyloctyl)-3-hydroxy-
naphthalene-1,4-dione (6)17 and (S)-2-hydroxy-3-(8,8,8-trifluoro-2-methyloctyl)naphthalene-1,4-dione (“NQ1”)
(7)12,13 (Figure 2). The S configuration was predicated by a protein modeling study of the interaction of 5 with
the Rieske iron-sulfur protein.12 Both 6 and 7 are more active than atovaquone, and 7 strongly inhibits
atovaquone-resistant Plasmodium falciparum sporozoites. The IC50 data against Plasmodium berghei are
shown for 5 and 7 in Figure 2.13 However, 7 exhibits significantly lower species selectivity than 5.12,13
Atovaquone has IC50 = 19.7 nM, and 6 has not yet been tested.
Figure 2. Structures of antimalarial naphthoquinones 5-7
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Results and Discussion
Our initial synthesis of 617 involved the preparation of (S)-8-fluoro-2-methyloctanal (16) and subsequent
condensation with 2-hydroxy-1,4-naphthoquinone (17) using our three-component reductive alkylation
method,19 to afford 6 in excellent yield (Scheme 1). Thus, synthesis of the known 8-fluorooctanoic acid (11),18
acid chloride formation, and the Evans chiral auxiliary methodology20 with (S)-4-benzyl-2-oxazolidinone (12),
and asymmetric C-2 methylation20-22 of 13, afforded 14 in good overall yield from 11. Interestingly, ester
formation from the commercially available 8-bromooctanoic acid (8) gave 9 as a mixture of bromide and
iodide, which was converted into fluoride 10. Reduction of 14 and oxidation of alcohol 15 gave the desired
(S)-8-fluoro-2-methyloctanal (16).17
Scheme 1. Synthesis of (S)-2-(8-fluoro-2-methyloctyl)-3-hydroxynaphthalene-1,4-dione (6)17
We now describe an alternative synthesis of 6 via the new compounds (S)-8-bromo-2-methyloctanal (24)
and (S)-2-(8-bromo-2-methyloctyl)-3-hydroxynaphthalene-1,4-dione (25) (Scheme 2), which avoids the
intermediacy of the toxic octyl fluorides 10 and 11 (Krebs cycle poisons comparable to fluoroacetic acid).18
Furthermore, substitution of bromine should allow for further functionalization of this -position. The
chemistry follows that in Scheme 1 starting with 8-bromooctanoic acid (8) and affords 25 in good overall yield.
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Scheme 2. Synthesis of (S)-2-(8-bromo-2-methyloctyl)-3-hydroxynaphthalene-1,4-dione (25)
Our syntheses of 5 and 7 take a different path from those of 6 and 25, and are described in Schemes 3 and
4, respectively. In place of our three-component reductive alkylation of an aldehyde (i.e., 16 + 17 + 18,
Scheme 1), we employed tin-mediated coupling of the requisite alkyl iodide to 2-hydroxy-1,4-naphthalene-1,4-
dione sulfonate 30. The conversion of propanoate 26 to iodide 29 is known23 and sulfonate 30 was prepared
from 2-hydroxy-1,4-naphthalene-1,4-dione (17) (using PhSO2Cl, K2CO3, DMF, rt) in 78% yield. Whereas Fieser
synthesized racemic 5 in 1948 (“10576”), our synthesis of (S)-5 is the first to be described of this biologically
active stereoisomer (Scheme 3).
Scheme 3. Synthesis of (S)-2-hydroxy-3-(2-methyloctyl)naphthalene-1,4-dione (5) (S-10576)
Similar methodology was used to synthesize 7 (NQ1) (Scheme 4).11 Tosylate 27 was treated with Grignard
31, as prepared from 5-bromopentanoic acid in two steps with sulfur tetrafluoride24,25 and Mg, to afford 32 in
50% yield. Conversion of 32 to iodide 33 and coupling with quinone sulfonate 30 gave the desired 7 (NQ1) in
low yield. We prepared iodide 33 from 32 as we described in Scheme 3 for iodide 29.
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Scheme 4. Synthesis of (S)-2-hydroxy-3-(8,8,8-trifluoro-2-methyloctyl)naphthalene-1,4-dione (7) (NQ1)
Protein modeling studies suggested that the 8-methyl analogues might show improved activity, via non-
covalent interactions between this methyl group and Cys-180 of the Rieske iron-sulfur protein and cytochrome
b in the ubiquinol oxidation pocket.11 We have prepared (S)-3-hydroxy-5-methyl-2-(8,8,8-trifluoro-2-methyl-
octyl)naphthalene-1,4-dione (39) (NQ3)11 using the tin coupling method shown in Schemes 3 and 4. Thus, we
synthesized 2-methoxy-8-methylnaphthalene-1,4-dione (37) from 2-methoxyhydroquinone (34) via known
chemistry (oxidation,26,27 Diels-Alder cycloaddition,28 and aerial oxidation28) and coupled it with 33 as shown in
29
Scheme 5. Demethylation with BBr3 afforded 39 in low yield. Interestingly, the sulfonate corresponding to
38 could not be hydrolyzed with KOH to 39, in contrast to the results in Schemes 3 and 4. Disappointingly,
analogue 39 (NQ3) shows much weaker activity against Plasmodium berghei (IC50 >4400 nM) than we
expected.13
Scheme 5. Synthesis of (S)-3-hydroxy-5-methyl-2-(8,8,8-trifluoro-2-methyloctyl)naphthalene-1,4-dione (39) (NQ3)
Finally, we synthesized compound 43 (NQ2), the defluorinated version of 39, as shown in Scheme 6.
2-Methoxy-8-methylnaphthalene-1,4-dione (37) was converted into sulfonate 41 and coupled with iodide 29
as described in Scheme 3 for 5 to give 43 (NQ2) in low yield. As was the case for 39 (NQ3), analogue 43 (NQ2)
shows much weaker activity (IC50 247 nM) than (S)-5 against Plasmodium berghei than we expected based on
the protein modeling mentioned above.13
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Scheme 6. Synthesis of (S)-3-hydroxy-5-methyl-2-(2-methyloctyl)naphthalene-1,4-dione (43) (NQ2)
Conclusions
We describe the first synthesis of (S)-2-hydroxy-3-(2-methyloctyl)naphthalene-1,4-dione (S-5), the biologically
active enantiomer of the racemate “10576” (“M-285”) that Fieser synthesized more than 70 years ago. This
compound shows improved activity over atovaquone, which has been used to treat malaria and pneumonia
(Pneumocystis) pathogens since the mid 1990s as “Malarone,” a combination drug containing atovaquone and
proguanil. In fact, the Center for Disease Control (CDC) has recommended Malarone for Americans traveling
to nearly all malaria-endemic countries. However, these pathogens soon became resistant to atovaquone and
new drugs are greatly needed.30,31
By blocking the terminal oxidative metabolism of S-5 with a trifluoromethyl group (7) (NQ1) we have show
that this latter compound is a new lead in the design of improved hydroxy-naphthalene-1,4-dione
therapeutics, with 5-6 times greater activity against Plasmodium berghei than S-5. Both 6 and 7 are more
active than atovaquone, and 7 strongly inhibits atovaquone-resistant Plasmodium falciparum sporozoites. The
precise activity of (S)-2-(8-fluoro-2-methyloctyl)-3-hydroxynaphthalene-1,4-dione (6) remains to be
established, but it too would be expected to block terminal group metabolism. We have also shown that the
presence of an 8-methyl group in these compounds (39 and 43) does not lead to improved activity as our
protein modeling seemed to suggest.
In Figure 3, we show some additional non-fluorinated compounds that we have synthesized (unpublished)
and their IC50 activity. Activity below 200 nM is considered to be significant. Importantly, the activity of R-5 is
nearly 30 times less that that of S-5 against the yeast bc1 complex. The difference in activity between the two
epimers of 5 is believed to involve different interactions of the 2-methyloctyl side chain with the binding
groove of the yeast cytochrome bc1 complex. Whereas both the S and R isomers of 5 show a strong
hydrophobic interaction with valine-146 in the protein complex, the S-5 interaction constrains the rotation of
the “loose end” of the side chain in the protein binding groove and allows for stronger binding than does the
R-5 epimer by nearly a factor of 30.11
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Figure 3. Structures of 2-hydroxynaphthalene-1,4-diones and IC50 (nM) against the yeast bc1 complex
Experimental Section
General. All reactions were performed under positive nitrogen pressure in oven-dried glassware. Reactions
were monitored by thin-layer chromatography (TLC) on silica gel plates (0.25 mm) and visualized under
shortwave UV light at 254 nm or by staining with p-anisaldehyde or KMnO4 and heating. Unless otherwise
noted, all organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo as a standard
work-up procedure. Column chromatography was run using silica gel with particle size 40-63 μm. Melting
points were measured using the Mel Temp apparatus of Laboratory Devices with samples prepared in open
capillary tubes. Mass spectra were performed by the SCS Mass Spectrometry lab at the University of Illinois.
1
IR spectra were obtained by using a Jasco FT/IR-4100 spectrometer. H and 13C NMR spectra were recorded at
600 MHz and 150 MHz, respectively, using Bruker Avance III HD 600 spectrometer. Chemical shifts () were
reported in parts per million (ppm) using the residual signal of the solvent as an internal reference (CDCl3, H
7.26; C 77.23). Multiplicities were reported using the following abbreviations: singlet (s), doublet (d), triplet
(t), quartet (q), multiplet (m), and broad (br).
(S)-4-Benzyl-3-(8-bromooctanoyl)oxazolidin-2-one (20). To a solution of 8-bromooctanoic acid (8) (4.13 g,
18.5 mmol) in CH2Cl2 (200 mL), oxalyl chloride (8 mL, 93 mmol) was added. The reaction mixture was stirred
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overnight. The crude acyl chloride 19 was concentrated in vacuo and stored under vacuum. In a separate
round-bottomed flask, a solution of (S)-4-benzyloxazolidin-2-one (12) (4.26 g, 18.5 mmol) and DMAP (0.27 g,
2.2 mmol) in CH2Cl2 (200 mL) was stirred at 0 °C. Then Et3N (9.7 mL, 69 mmol) was added dropwise into the
reaction mixture, followed by the above acyl chloride in CH2Cl2 (10 mL). The reaction was stirred overnight,
and after TLC confirmed completion, the reaction was concentrated in vacuo and covered with EtOAc (100
mL). The solution was extracted with EtOAc, washed with 3% HCl (100 mL), saturated NaHCO3 (100 mL), and
brine (100 mL), and dried. It was finally concentrated in vacuo, then purified using flash chromatography to
1
give 20 as a thick oil, 5.67 g (80% from 8): [
α
]D +37°; H NMR (CDCl3)  7.20-7.34 (5H, m), 4.67 (1H, m), 4.15-
4.21 (2H, m), 3.41 (2H, t, J 7 Hz), 3.28-3.31 (1H, dd, J 13, 3 Hz), 2.90 (1H, m), 2.95 (1H, m), 2.75-2.79 (1H, dd, J
13
13, 10 Hz), 1.87 (2H, m, 7 Hz), 1.70 (2H, m, 6 Hz), 1.37-1.46 (6H, m); C NMR (CDCl3)  173.5, 153.7, 135.5,
129.6, 129.2, 127.6, 66.4, 55.4, 38.1, 35.7, 34.1, 32.9, 29.1, 28.7, 28.2, 24.3; IR: νmax (cm-1) 2930, 1780,
1700, 1390, 1210, 701. Anal. HRMS m/z Calcd for C18H25BrNO3 (M + H): 382.1018. Found: 382.1013.
(S)-4-Benzyl-3-((S)-8-bromo-2-methyloctanoyl)oxazolidin-2-one (21). To a solution of NaHMDS (26 mL, 26.3
mmol) in THF (200 mL) while stirred at -78 °C, a pre-cooled solution of the oxazolidinone 20 (8.37 g, 21.9
mmol) in THF (50 mL) was added dropwise. After an hour of stirring, methyl iodide (6.8 mL, 110 mmol) was
added dropwise, and the reaction mixture was stirred for 4 h at the same temperature. Upon completion of
the reaction as indicated by TLC, the reaction mixture was quenched with saturated NH4Cl (aq). After the
solvent was removed in vacuo, the mixture was extracted with CH2Cl2, washed consecutively with 5% KHSO4,
saturated Na2S2O3, and brine, dried, and concentrated in vacuo. The crude product was purified by flash
chromatography using ethyl acetate and hexanes, affording 6.51 g (75%) of 21 as a thick, colorless oil: [α]
D
+33°; 1H NMR (CDCl3)  7.20-7.33 (5H, m), 4.68 (1H, m), 4.17-4.20 (2H, m); 3.70 (1H, m, J 7 Hz), 3.41 (2H, t, J
6 Hz), 3.27 (1H, dd, J 13, 4 Hz), 2.77 (1H, dd, 13, J 9 Hz), 1.84 (2H, m, J 7 Hz), 1.75 (1H, m, J 6.17 Hz), 1.42
13
(3H, m, J 6.17 Hz), 1.32 (4H, m, J 2.94 Hz), 1.21 (3H, d, J 6.81 Hz); C NMR (CDCl3)  177.4, 153.3, 135.5,
129.7, 129.2, 127.6, 66.2, 55.6, 38.1, 37.9, 34.1, 33.5, 32.9, 29.0, 28.2, 27.3, 17.6; IR: νmax (cm-1) 2930, 2360,
1780, 1700, 1390, 1210. Anal. HRMS m/z Calcd for C19H27BrNO3 (M + H)+: 396.1174. Found: 396.1165.
(S)-8-Bromo-2-methyloctanoic acid (22). To a solution of 21 (0.66 g, 1.67 mmol) in THF-water (40 mL) in 3:1
ratio stirring at 0 °C, H2O2 (30%, 1.6 mL, 16 mmol) was added. After 10 min, LiOH·H2O (0.14 g, 3.33 mmol) was
added. The reaction mixture was stirred for 3 h, then quenched with Na2SO3. The solution was washed with
EtOAc and separated. The aqueous solution was covered with EtOAc and acidified to pH 2 with 5% KHSO4. The
organic layer was extracted with EtOAc, washed with brine, dried, and concentrated in vacuo to give 22 (0.33
g, 83%), as a colorless liquid, which was used in the next step without further purification: [α
]D +4.4°; 1H NMR
(CDCl3)  11.2 (1H, br s), 3.40 (2H, t, J 7 Hz), 2.47 (1H, m, J 7 Hz), 1.85 (2H, m, J 7 Hz), 1.66 (1H, m, J 7 Hz),
1.43 (3H, m, J 7 Hz), 1.33 (4H, m, J 5 Hz), 1.18 (3H, d, J 8 Hz); 13C NMR (CDCl3)  182.5, 39.4, 34.1, 33.6, 32.9,
28.9, 28.2, 27.2, 17.1; IR: νmax (cm-1) 2935, 2858, 1704, 1464, 1241, 941. Anal. HRMS m/z Calcd for
C9H18BrO2: 237.0490. Found: 237.0489.
(S)-8-Bromo-2-methyl-1-octanol (23). To a stirred solution of 22 (1.0 eq) in dry ether at 0 °C, LiAlH4 (3.0 eq, 4.0
M solution in dry ether) was added dropwise. The mixture was stirred overnight. After quenching with water,
the mixture was extracted with diethyl ether, washed with brine, dried, and concentrated in vacuo. The crude
1
product 23, as a colorless liquid, was used in the next step without further purification: [
α
]D +88°; H NMR
(CDCl3)  3.49- 3.52 (1H, dd, J 10, 6 Hz), 3.40-3.44 (3H, m), 1.83-1.87 (2H, m, J 7 Hz), 1.26-1.45 (9H, m); IR:
νmax (cm-1) 3340, 2928, 1464, 1260, 1040, 646.
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(S)-8-Bromo-2-methyloctanal (24). To a stirred solution of oxalyl chloride (1.37 mL, 16.0 mmol) in 5 mL of
CH2Cl2 at -78 °C, DMSO (2.27 mL, 32.0 mmol) was added dropwise. After stirring for 15 min, a solution of 23
(1.19 g, 5.33 mmol) in 10 mL CH2Cl2 and Et3N (6.69 mL, 48.0 mmol) were added consecutively. The solution
was stirred for 45 min while warming up to room temperature. The solution was quenched with water,
extracted with CH2Cl2, washed with brine, dried, and concentrated in vacuo. The crude product was purified
via flash chromatography, affording 1.1 g (93%) of 24 as a colorless liquid, [α
]D +9°; 1H NMR (CDCl3)  9.61 (1H,
d, J 2 Hz), 3.40 (2H, t, J 7 Hz), 2.33 (1H, m), 1.85 (2H, m, J 7 Hz), 1.71 (1H, m, J 6 Hz), 1.33-1.46 (7H, m), 1.10
13
(3H, d, J 7 Hz); C NMR (CDCl3)  182.2, 161.1, 71.2, 39.4, 35.9, 34.1, 33.6 32.9, 28.9, 28.2, 27.2, 25.3,
20.2, 17.1; IR: νmax (cm-1) 2933, 2858, 1703, 1463. Anal. HRMS m/z Calcd for C9H16BrO (M + H)+: 219.0385.
Found: 219.0383.
(S)-2-(8-Bromo-2-methyloctyl)-3-hydroxynaphthalene-1,4-dione (25). In a round-bottom flask equipped with
a stirring bar, aldehyde 24 (2.0 eq), 2-hydroxynaphthalene-1,4-dione (17) (1.0 eq), the Hantzsch ester (1.0 eq),
and L-proline (0.5 eq) were all combined together in CH2Cl2 and stirred at rt for 48 h. The reaction mixture was
concentrated in vacuo, then purified via flash column chromatography using hexanes and EtOAc to give 25
(78%) as a yellow solid: mp 81-82 °C; [α]D = +0.9°; 1H NMR (CDCl3)
 8.07-8.12 (2H, dd, J 7 Hz), 7.66-7.76 (2H,
dt, J 8 Hz), 7.33 (1H, s), 3.39 (2H, t, J 7 Hz), 2.57-2.61 (1H, dd, J 6 Hz), 2.42-2.45 (1H, dd, J 8 Hz), 1.81-1.85 (3H,
m, J 8 Hz), 1.29-1.42 (8H, m), 0.88 (3H, d, J 7 Hz); 13C NMR (CDCl3)  185.1, 181.6, 153.7, 135.1, 133.2, 133.1,
129.7, 127.0, 126.3, 124.2, 37.3, 34.2, 33.0, 32.95, 30.9, 29.1, 28.4, 27.06, 19.9; IR: νmax (cm-1) 3350, 2900,
1630, 1600, 1350, 1250, 700. Anal. HRMS m/z Calcd for C19H24BrO3 (M + H)+ 379.0909. Found: 379.0894.
(S)-2-Hydroxy-3-(8,8,8-trifluoro-2-methyloctyl)naphthalene-1,4-dione (7) (NQ1). Yield 20 mg (4%); mp 87–89
1
°C.; [α]D CH2Cl2 –1.3 (c = 1); H NMR (CDCl3)  8.14–8.09 (dd, J 8.0 Hz, 2H, H-5, H-8), 7.68–7.79 (2H, H-6, H-7),
7.79–7.68 (m, 2H, H-6, H-7), 7.30 (br, 1H, OH), 2.43–2.63 (m, 4H), 2.09–2.04 (m, 2H, CH2), 1.86 (br, 1H, CH),
1.36–1.24 (br, 10H, (CH2)5); 19F NMR (CDCl3)  –66.8 (t, J 11.8 Hz); (EI) m/z 354 (88%) (M)+. Anal. HRMS Calcd
for C19H21F3O3 354.1443. Found: 354.1442.
(S)-3-Hydroxy-5-methyl-2-(8,8,8-trifluoro-2-methyloctyl)naphthalene-1,4-dione (39) (NQ3). Yield 1 mg (4%);
1H NMR (CDCl3)  8.19–8.18 (d, J 2 Hz, 1H, H-5), 7.64–7.62 (2H, H-6, H-7), 7.57 (br, 1H, OH), 2.93 (s, 3H, CH3),
2.78 (s, 3H, CH3), 2.41–2.58 (m, 4H), 2.11–2.04 (m, 2H, CH2), 1.86 (br, 1H, CH), 1.36–1.24 (br, 10H, (CH2)5). 19F
NMR (CDCl3) δ –66.8 (t, J 12 Hz). (EI) m/z 368 (88%) (M+H+). Anal. HRMS Calcd for C20H23F3O3: 368.1599.
Found: 368.1604.
S-2-Hydroxy-3-(2-methyloctyl)-8-methylnaphthalene-1,4-dione (43) (NQ2). Yield 5 mg (11%): mp 53–55 °C;
1H NMR (CDCl3)  8.19–8.18 (d, J 2 Hz, 1H, H-5), 7.64–7.62 (2H, H-6, H-7), 7.57 (br, 1H, OH), 2.67–2.43 (m, 2H,
CH2), 1.86 (br, 1H, CH), 1.40–1.19 (br, 10H, (CH2)5), 0.93–0.88 (m, 6H, CH3, CH3); (EI) m/z 314 (82%); Anal.
HRMS Calcd for C20H26O3: 314.1882. Found: 314.1880.
Acknowledgements
We acknowledge and thank Dartmouth College for support of this work, and E.E.K. acknowledges a Zabriskie
Fellowship from Dartmouth College. We recognize the late Bernard L. Trumpower for the genesis of this
project. He is greatly missed.
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